This is a resubmission of an RO1 application for three years of funding to investigate the role of iron and dopamine in pathophysiology of restless legs syndrome (RLS), a common sleep disorder, especially for older patients. The disease carries a considerable morbidity with severe sleep disturbance due to distressing sensations in the legs, particularly while resting and in the evening. The pathophysiology of the disorder has not been identified. There are reports suggesting involvement of dopamine pathways and iron storage in the brain. Patients often improve with low doses of L-dopa and dopamine agonists. Iron is needed for production of dopamine. Hence, there may be a defect in the brain iron transport or storage in RLS. The pilot data during the period of least symptoms showed significantly lower cerebrospinal fluid (CSF) ferritin levels in the patients than in controls and a non-significant decrease in dopamine metabolites. These findings need to be confirmed with a larger sample, particularly when the patients have maximum symptoms. The authors hypothesized that CSF ferritin and magnetic resonance imaging (MRI) of the brain iron measures will be lower for RLS patients during the period of maximum symptoms than in controls. The authors would also explore relationships between iron and CSF measures of dopaminergic activities, which could provide the basis for entirely new research and treatment approaches to RLS.